Compositions for the relief of xerostomia and the treatment of associated disorders

ABSTRACT

New liquid compositions are described for the relief of the xerostomia and the treatment of associated disorders, in which the compositions contain: a) saline saliva substitute agents selected from the group consisting of sodium chloride, potassium chloride, sodium bicarbonate, monobasic potassium phosphate, and dibasic phosphate potassium; b) saliva production stimulation agents selected from the group consisting of citric acid or its alkali metal salts and malic acid or its alkali metal salts; c) oral antiseptics selected from the group consisting of triclosan, chlorhexidine and its salts, benzalkonium and its salts, and cetylpyridinium chloride; d) anticariogenic agents selected from the group consisting of fluoride sodium, sodium monofluorophosphate, and xylitol; and e) oral mucosa protective agents selected from the group consisting of vitamin E acetate, panthenol, dipotassium glycyrrhizinate and extracts of aloe vera. 
     The aforementioned compositions are presented in the form of mouthwashes, sprays, oral gels, and toothpastes.

CROSS-REFERENCE TO RELATED APPLICATION

This Application is a 371 of PCT/ES02/00443, filed Sep. 19, 2002; thedisclosure of which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention refers to new compositions for the relief ofxerostomia or “dry mouth,” which are also simultaneously useful for thetreatment of disorders caused by this condition.

PRIOR ART

Xerostomia, or “dry mouth,” is a symptomatic manifestation caused by adecrease in the activity of the salivary glands. The reduction in salivaformation causes individuals who suffer from this condition to havedifficulty for eating, talking, chewing, etc. Even in less acute cases,the feeling of dry mouth is very unpleasant.

Xerostomia can be associated with various kinds of disorders, of whichSjörgren's syndrome is the most well-known, or can be due to exogenouscauses, such as the consumption of tobacco and alcohol, the side effectsof some kinds of drugs, e.g., antidepressants or diuretics, particularlyin individuals receiving multiple drug therapies, or it can be due toradiotherapy and chemotherapy treatments in cancer patients.

In older individuals, xerostomia is a widespread symptom, and someauthors consider that the incidence of “dry mouth” in persons over 55years of age can be as high as 40%.

In addition, the decrease in salivary secretion typically causesassociated disorders, including gingivitis, cavity formation, and theappearance of canker sores.

The numerous patents and patent applications referring specifically topreparations for alleviating xerostomia include the following:

U.S. Pat. No. 4,088,788 describes chewing gums to stimulate salivationcontaining a combination of an organic acid and saccharin.

U.S. Pat. No. 4,820,506 describes a liquid composition administered inaerosol spray that contains citric acid, calcium phosphate, and afood-grade sweetener, preferably aspartame.

EP396634-B1 describes a chewing gum that contains adipic acid, insteadof citric acid, as the main ingredient for stimulating salivaproduction.

EP413427-B1 describes the specific use of xylitol, in the absence offood-grade organic acids, for the treatment of xerostomia. The ediblecompositions described are primarily chewing gums.

EP613684-B1 describes solid forms for the treatment of xerostomia,tablets or chewing gums, which contain polyethylene oxide as alubricating polymer, citric acid, sources of mineral salts, and a sourceof fluorides.

U.S. Pat. No. 5,541,165 describes a saliva substitute composition thatcontains glycerin, a gum, e.g., xanthan, that can also include a buffersystem based on citric acid or citrates and carbonate.

U.S. Pat. No. 5,510,122 describes a natural complete saliva compositionthat is treated exogenously with a disinfectant such as chlorhexidine orionising radiation.

U.S. Pat. No. 6,159,459 describes an oral lubricant having particularusefulness for treating xerostomia based on a beta-glucan polymer.

EP745385-A2 describes a moistening composition to alleviate “dry mouth”containing an edible organic acid, such as citric or malic acid, and asource of calcium ions in phosphate form.

WO9944573 describes a tablet capable of increasing saliva productionthat contains an algae ingredient capable of absorbing water and apectin-rich ingredient with a relatively low solubility.

As shown above, a significant number of proposals have been made tosolve the problem of alleviating “dry mouth,” which clearly indicatesthat there are no perfect solutions for this condition.

No solutions are observed to treat the problem globally, i.e., by alsotaking into account the specific treatment of disorders caused byxerostomia: gingivitis, cavity formation, and the appearance of cankersores.

Therefore, there is still a need to find alternative treatments to thosedescribed which would offer a greater range of possibilities for reliefto individuals suffering from “dry mouth” and which would allowsimultaneous treatment of the inherent symptoms and the subsequentdisorders caused by these symptoms.

OBJECT OF THE INVENTION

The object of this invention consists of fluid, liquid or pastecompositions containing saliva formation stimulation agents, salivasubstitutes, antiseptics, anticariogenic agents, and oral mucosaprotective agents which alleviate the symptoms of xerostomia or “drymouth,” as well as disorders associated with this condition,particularly gingivitis, cavity formation, and the appearance of cankersores.

DESCRIPTION OF THE INVENTION

The compositions contemplated in the invention are liquid or pastefluids that are characterised by comprising the following:

-   -   a) one or more saline saliva substitutes selected from the group        consisting of sodium chloride, potassium chloride, sodium        bicarbonate, monobasic potassium phosphate, and dibasic        potassium phosphate,    -   b) one or more saliva production stimulation agents selected        from the group of citric acid or its alkali metal salts and        malic acid or its alkali metal salts,    -   c) one or more oral antiseptics selected from the group        consisting of triclosan, chlorhexidine and its salts,        benzalkonium and its salts, and cetylpyridium chloride.    -   d) one or more anticariogenic agents selected from the group        consisting of fluoride sodium, sodium monofluorophosphate, and        xylitol,    -   e) one or more oral mucosa protective agents selected from the        group of vitamin E acetate, panthenol, dipotassium        glycyrrhizinate, and aloe vera extracts, and    -   f) water and/or polyols acceptable for human consumption.

The compositions contemplated in the invention are for topical use andcan be formulated in the form of mouthwashes, sprays, oral gels, andtoothpastes, with the help of the conventional ingredients used forthese topical forms, well known by those skilled in the art.

The saline saliva substitutes agents mentioned above are found innatural saliva, help provide the buffering and chelating effect thatpromotes remineralisation of tooth enamel, and prevent saliva pH fromentering the acid region that encourages the development of cavities.

Preferably, in the compositions contemplated in the invention, the sumof the quantities of sodium chloride, potassium chloride, monobasicpotassium phosphate, and dibasic potassium phosphate represents between0.2% and 1.0% with respect to the total volume of the composition in thecase of a liquid and with respect to the total weight thereof in thecase of a paste (hereinafter expressed as weight/volume). Sodiumbicarbonate, when present, preferably represents between 1% and 3% withrespect to the total weight/volume of the composition.

Among the oral antiseptics selected, the preferred antiseptic istriclosan—a known antibacterial agent which has antiseptic activityagainst pathogenic microorganisms responsible for periodontitis and hasrecently been proven to also reduce inflammation of the gum tissues.

Preferably, the concentrations of mouthwash contained in thecompositions of the invention are between 0.1% and 1.0% of antiseptic,with respect to the total weight/volume thereof.

Citric acid and malic acid cause direct stimulation of saliva secretion,although they have an adverse effect on tooth enamel due to the decreasein pH which causes demineralisation. As a result, it is preferable toformulate the aforementioned acids along with their alkali salts, whichprevents an excessive decrease of pH without losing efficacy in terms ofthe stimulation of saliva production.

Preferably, the compositions contemplated in the invention containbetween 0.1% and 0.3%, with respect to the total weight/volume thereof,of the sum of saliva production stimulation agents selected.

The anticariogenic effect of fluoride compounds, such as fluoride sodium(NaF) and sodium monofluorophosphate, also known as NaMFP, iswell-known.

Preferably, the compositions contemplated in the invention containbetween 0.5% and 2.0%, with respect to the total weight/volume thereof,of the sum of fluoridated compounds selected.

Xylitol is a natural sugar that is not fermented by cariogenic bacteriain acidic medium, and therefore has no cariogenic effect. In addition,it has in fact its own anticariogenic effect, as it inhibits the growthof certain bacteria present in the mouth and also helps reducedemineralization of the enamel by interfering with the transport ofhydroxyapatite from the lesion to the saliva.

Preferably, the compositions contemplated in the invention containbetween 1% and 10% of xylitol, with respect to the total weight/volumethereof.

Due to its buffering role which decreases acidity, bicarbonate alsocontributes to a anticariogenic effect.

Among the protective agents for the oral mucosa, particularly thegingival mucosa, selected for the purposes of this invention:

-   -   Vitamin E acetate improves blood circulation and inhibits        inflammation, as it can inhibit the biosynthesis of        prostaglandins. Therefore, gum inflammation and bleeding are        reduced if vitamin E is included in daily oral hygiene. In        addition, topical treatment with vitamin E accelerates the        healing of oral wounds.    -   Panthenol is a pantothenic acid derivative that promotes the        healing process by epidermal stimulation without causing        sensitisation or irritation.    -   The extracts of aloe vera are natural products of proven        efficacy that inhibit inflammation, improving the healing of        wounds.    -   Dipotassium glycyrrhizinate is the dipotassium salt of the        triterpenic heteroside extracted from the root of Glycyrrhiza        glabra and has anti-inflammatory and healing activity, improving        the conditions of the general epithelium and reducing        inflammation and bleeding. In addition, dipotassium        glycyrrhizinate has sweetener and surfactant properties, along        with some capacity to inhibit the formation of dental plaque.

Preferably, the sum of the mucosa protective agents selected representsbetween 0.2% and 2.0%, calculated as pure products, with respect to thetotal weight/volume of the compositions contemplated in the invention.

Especially preferably, the compositions contemplated in the inventioncontain extract of aloe vera, in proportions between 0.01% and 0.5%expressed as concentrated pure product in solid form with respect to thetotal weight/volume of the composition.

The compositions contemplated in the invention are completed with waterand/or polyols acceptable for human consumption, among them glycerine,sorbitol, and/or propylene glycol, as well as with other, nonessentialingredients of those conventionally used in oral liquid compositions.

As mentioned earlier, the compositions contemplated in the invention arepresented in the form of mouthwashes, sprays, oral gels, andtoothpastes.

As known to those skilled in the art, mouthwashes are aqueous orwater-alcohol solutions for rinsing the mouth which have a well-known,conventional formulation. In addition to water, polyhydroxylatedcompounds such as glycerine or glycols (e.g., propylene glycol, nonionicsurfactants, etc.) and other additives to improve appearance, flavour,and preservation can be included.

The sprays are compositions equal or similar to mouthwashes butdispensed in spray bottles for convenient application of the dose neededto moisten and protect the mouth without requiring subsequent rinsing.

Oral gels also include polymers that gel the compositions, which allowsdirect, stable application to the oral cavity. In relation to thesepolymers, for the purposes of this invention it is preferable to use acombination of polymers generically known as polycarbophil and carbomer,since they keep the gel structure stable for very prolonged times underextreme temperature conditions. The gels can also include a quantity ofa natural, noncariogenic sweetener, such as sorbitol.

The formulation of toothpastes is well-known by those skilled in theart. In the toothpaste compositions contemplated in the invention, it ispreferable to use nonionic (e.g., fatty acids esters with sugars) oramphoteric (e.g., coco-derived betaines) surfactants, since anionicsurfactants have a negative effect on the delicate epithelial tissue ofthe gums in the cases of xerostomia. In the case of toothpastes, the useof sodium bicarbonate to neutralise oral acidity is also particularlypreferred.

In addition, toothpastes can contain thickening agents such as xanthangum, abrasive silica fillers, and other supplementary agents in additionto those normally used in the toothpaste industry.

The compositions contemplated in the invention are prepared byconventional mixing techniques, well-known to those skilled in the art,and provide fast, effective, sustained relief to individuals sufferingfrom xerostomia, while also decreasing the incidence of cavities,gingivitis and canker sores in this type of patient.

The examples shown below are presented for the purposes of providingthose skilled in the art with a sufficiently clear and completeexplanation of this invention, but should not be considered limitationson the essential aspects contemplated therein, as presented in earliersections of this description.

EXAMPLES Example 1 Composition in the Form of Mouthwash and Spray

By mixing and dissolving the ingredients, a mouthwash is prepared withthe following composition, expressed in terms of the percentage contentof each ingredient with respect to the total volume of the composition:

a) Saline saliva substitutes Sodium chloride 0.09 Potassium chloride0.06 Dipotassium phosphate 0.08 Monopotassium phosphate 0.03 b)Stimulation agents for saliva production Citric acid 0.05 Malic acid0.04 Sodium citrate 0.10 c) Antiseptic Triclosan 0.15 d) Anticariogenicagents Fluoride sodium 0.10 Sodium monofluorophosphate 0.80 Xylitol 8.00e) Oral mucosa protective agents Aloe barbadensis powder 200:1 0.05Dipotassium glycyrrhizinate 0.03 Panthenol 0.20 Tocopherol acetate(vitamin E) 0.20 f) Other ingredients of the formula Glycerine 5.00Disodium EDTA 0.03 Propylene glycol 7.00 Hydrogenated castor oil PEG-40as nonionic surfactant 2.00 (Commercial reference: CREMOPHOR RH-40)Preservatives <1.00 Colorants, flavourings <0.10 Purified water q.s.100.00 ml

-   -   Physical and chemical characterisation of the product:    -   Direct pH: 5.5±0.3    -   Density at 20° C.: 1.057 mg/ml

Example 2 Composition in the Form of an Oral Gel

By mixing the ingredients, an oral gel is prepared with the followingcomposition, expressed in terms of the percentage content of eachingredient with respect to the total volume of the composition:

a) Sailne saliva substitutes Sodium chloride 0.09 Potassium chloride0.06 Dipotassium phosphate 0.08 Monopotassium phosphate 0.03 b)Stimulation agents for saliva production Citric acid 0.05 Malic acid0.05 Sodium citrate 0.05 c) Antiseptic Triclosan 0.15 d) Anticariogenicagents Fluoride sodium 0.06 Sodium monofluorophosphate 0.16 Xylitol 8.00e) Oral mucosa protective agents Aloe barbadensis powder 200:1 0.10Dipotassium glycyrrhizinate 0.10 Panthenol 0.20 Tocopherol acetate(vitamin E) 0.20 f) Other ingredients of the formula Polycarbophil(Commercial reference: NOVEON AA-1) 1.00 Carbomer (Commercial reference:CARBOPOL 980-NF) 1.00 Disodium EDTA 0.20 Sodium hydroxide 40% 1.00Propylene glycol 7.00 Hydrogenated castor oil PEG-40 as nonionicsurfactant (Commercial reference: CREMOPHOR RH-40) 2.50 Sorbitol 45.00Preservatives <1.00 Colorants, flavourings <0.10 Purified water q.s.100.00

-   -   Physical and chemical characteristics:    -   pH (10%): 5.5±0.3    -   Density at 20° C.: 1.195 g/ml    -   Dynamic viscosity at 20° C.: D 100=8,300 mPa·s±500 mPa·s

Example 3 Composition in the Form of a Toothpaste

By mixing the ingredients, a toothpaste is prepared with the followingcomposition, expressed in terms of the percentage content of eachingredient with respect to the total volume of the composition:

a) Saline saliva substitutes Sodium chloride 0.09 Potassium chloride0.06 Dipotassium phosphate 0.08 Monopotassium phosphate 0.03 Sodiumbicarbonate 2.00 b) Stimulation agents for saliva production Sodiumcitrate 0.20 c) Antiseptic Triclosan 0.30 d) Anticariogenic agentsFluoride sodium 0.32 Sodium monofluorophosphate 0.80 Xylitol 2.00 e)Oral mucosa protective agents Aloe barbadensis powder 200:1 0.05Dipotassium glycyrrhizinate 0.15 Panthenol 0.20 Tocopherol acetate(vitamin E) 0.20 f) Other ingredients of the formula Xanthan gum 0.80Glycerine 12.00 Sorbitol 35.00 Dimethicone (Commercial reference:SILICEX SH fluid) 1.00 Sodium saccharin 0.15 Polyethylene glycol 4002.00 Flavourings <1.50 Silica (1) (Commercial reference: SORBOSIL TC-15)11.00 Silica (2) (Commercial reference: SORBOSIL AC-39) 6.00 Titaniumdioxide 1.50 Sucrose laurate as nonionic surfactant (Commercialreference: SISTERNA LC-70) 2.50 Cocamidopropyl betaine as amphotericsurfactant (Commercial reference: TEGO BETAIN ZF) 2.50 Preservatives<0.40% Purified water q.s. 100.00 g

-   -   Physical and chemical characteristics:    -   pH (10%): 8.8±0.3    -   Specific gravity at 20° C.: 1.33 g/ml±0.02 g/ml    -   Dynamic viscosity at 20° C.: D100: 4,500 Pa·s±500 mPa·s

1. A composition, for the relief of xerostomia and the treatment ofassociated disorders, consisting of: a) one or more saline salivasubstitute agents, selected from the group consisting of sodiumchloride, potassium chloride, sodium bicarbonate, monobasic potassiumphosphate, and dibasic potassium phosphate, b) one or more salivaproduction stimulation agents, selected from the group consisting ofcitric acid or its alkali metal salts and malic acid or its alkali metalsalts, c) one or more oral antiseptics selected from the groupconsisting of triclosan, chlorhexidine and its salts, benzalkonium andits salts, and cetylpyridium chloride, d) one or more anticariogenicagents selected from the group consisting of sodium fluoride, sodiummonofluorophosphate, and xylitol, e) one or more oral mucosa protectiveagents selected from the group consisting of vitamin E acetate,panthenol, dipotassium glycyrrhizinate, and an aloe vera extract, and f)water and/or polyol(s) acceptable for human consumption.
 2. Thecomposition according to claim 1, wherein the sum of sodium chloride,potassium chloride, monobasic potassium phosphate, and dibasic potassiumphosphate present is between 0.2% and 1.0% with respect to the totalweight/volume of the composition, and the quantity of sodiumbicarbonate, if present, is between 1% and 3% of the total weight/volumeof the composition.
 3. The composition according to claim 1, whereinsaid composition contains triclosan.
 4. The composition according toclaim 1 or 3, wherein said composition contains between 0.1% and 1.0% ofantiseptic with respect to the total weight/volume of the composition.5. The composition according to claim 1, wherein said compositioncontains saliva production stimulation agents in an amount of between0.1% and 0.3%, with respect to the total weight/volume of thecomposition.
 6. The composition according to claim 1, wherein saidcomposition contains sodium fluoridated and/or sodiummonofluorophosphate in an amount between 0.5% and 2.0%, with respect tothe total weight/volume of the composition.
 7. The composition accordingto claim 6, wherein said composition contains xylitol in an amount ofbetween 1% and 10% with respect to the total weight/volume of thecomposition.
 8. The composition according to claim 1, wherein saidcomposition contains oral mucosa protective agents in an amount ofbetween 0.2% and 2.0% with respect to the total weight/volume of thecomposition.
 9. The composition according to claims 1 or 8, wherein thecomposition contains an extract of aloe vera at proportions between0.01% and 0.5% expressed as pure concentrated product in solid form withrespect to the total weight/volume of the composition.
 10. Thecomposition according to claim 1, wherein said composition is amouthwash.
 11. The composition according to claim 1, wherein saidcomposition is a spray suitable for administration by a sprayer.
 12. Anoral gel composition for the relief of xerostomia and the treatment ofassociated disorders, consisting of: a) one or more saline salivasubstitute agents, selected from the group consisting of sodiumchloride, potassium chloride, sodium bicarbonate, monobasic potassiumphosphate, and dibasic potassium phosphate, b) one or more salivaproduction stimulation agents, selected from the group consisting ofcitric acid or its alkali metal salts and malic acid or its alkali metalsalts, c) one or more oral antiseptics selected from the groupconsisting of triclosan, chlorhexidine and its salts, benzalkonium andits salts, and cetylpyridium chloride, d) one or more anticariogenicagents selected from the group consisting of sodium fluoride, sodiummonofluorophosphate, and xylitol, e) one or more oral mucosa protectiveagents selected from the group consisting of vitamin E acetate,panthenol, dipotassium glycyrrhizinate, and an aloe vera extract, f)water and/or polyol(s) acceptable for human consumption; g) a blend ofpolycarbophil polymers and carbomer, and h) optionally containing anoncariogenic sweetner.
 13. A toothpaste composition for the relief ofxerostomia and the treatment of associated disorders, consisting of: a)one or more saline saliva substitute agents, selected from the groupconsisting of sodium chloride, potassium chloride, sodium bicarbonate,monobasic potassium phosphate, and dibasic potassium phosphate, b) oneor more saliva production stimulation agents, selected from the groupconsisting of citric acid or its alkali metal salts and malic acid orits alkali metal salts, c) one or more oral antiseptics selected fromthe group consisting of triclosan, chlorhexidine and its salts,benzalkonium and its salts, and cetylpyridium chloride, d) one or moreanticariogenic agents selected from the group consisting of sodiumfluoride, sodium monofluorophosphate, and xylitol, e) one or more oralmucosa protective agents selected from the group consisting of vitamin Eacetate, panthenol, dipotassium glycyrrhizinate, and an aloe veraextract, and f) water and/or polyol(s) acceptable for human consumption;g) nonionic and/or amphoteric surfactants, but not anionic surfactants;and h) optionally containing thickening agents.
 14. The compositionaccording to claim 13, wherein the composition contains sodiumbicarbonate.